The goal of these studies is to understand the basic molecular mechanisms that govern the initial recognition events in the immune response. As examples of these, we have focused on the interaction of the MHC class I molecule, complexed with self or viral peptides, with the T cell receptor, or with a receptor on natural killer cells, Ly-49. We have developed model systems for the study of this interaction both with purified protein molecules as well as with cellular T cell responses. Major accomplishments during the past year include: 1) development of a bacterial expression system in which a three domain T cell receptor is produced that maintains biochemical and immunological integrity, and in which biophysical parameters of binding parallel the biological activity of the molecule; 2) demonstration of the utility of such a three domain T cell receptor for specific blocking of T cell activation; 3) refinement of methodologies for the precise measurement of TCR/MHC/peptide interactions; 4) evaluation of the role of specific peptides in the interaction of the mouse MHC class I molecule H-2Dd with the NK cell receptor Ly-49A.